High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis.
In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or beta-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.
Studelska
Daniel R
DR
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mandik-Nayak
Laura
L
Zhou
Xiaodong
X
Pan
Jing
J
Weiser
Peter
P
McDowell
Lynda M
LM
Lu
Hong
H
Liapis
Helen
H
Allen
Paul M
PM
Shih
Fei F
FF
Zhang
Lijuan
L
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001324:Autoantigens / Q000276:immunology*; D055162:Biocatalysis; D002356:Cartilage / Q000378:metabolism; D004187:Disaccharides / Q000378:metabolism; D004195:Disease Models, Animal; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011485:Protein Binding; D013379:Substrate Specificity
D001324:Autoantigens; D004187:Disaccharides; D006025:Glycosaminoglycans; D005956:Glucose-6-Phosphate Isomerase